The primary goal of this project is to define immunological mechanisms of susceptibility and resistance to rabies virus in inbred strains of mice. A model system for analysis established by Dr. Donald Lodmell of this division is being used to characterize the cellular and humoral immune response of susceptible (A.SW, A/WySN) and resistant (SJL) strains of mice during infection with street rabies virus (SRV), a highly virulent strain that is lethal in susceptible hosts. Preliminary studies revealed a diminished in vitro T cell proliferative response in A.SWs as compared to SJLr hosts which was due to defective presentation of viral antigens, as antigen-pulsed macrophages from A.SWs or SJLr mice stimulated immune SJLr T cells equally well. A gradual decrease in spleen size A.SWs but not SJLr hosts was also noted. Attempts to define the basis for these observations led to immunofluorescent analyses of spleen lymphocyte subsets in these two strains of mice using a fluorescence activated cell sorter. FITC or phycoerythrin conjugated monoclonal antibodies (mAb) specific for T cells (anti-Thy 1.2 mAb), B cells (anti-kappa mAb), or I-A(+) cells (10-3.6 mAb) were used to strain spleen cells derived from mice at various times after SRV infection. Results indicate a dramatic (2-5 fold) decrease in all populations defined by these surface markers from two to seven days after infection in A.SWs but not SJLr hosts. Anti-SRV antibody responses, detected by RIA on intact virus using isotype-specific secondary antibody reagents, are also minimal in the susceptible animal. Efforts to protect A.SWs mice from rabies lethality by adoptive transfer of immune SJLr histocompatible cells have been unsuccessful, perhaps due to a paucity of IL-2 and other essential lymphokines in the infected A.SWs recipient. It has also been possible to convert SJLr mice to virus-susceptible hosts by induction of a CNS inflammatory response by pre-immunization with myelin basic protein, an encephalitogenic antigen. These studies provide valuable insights into the mechanisms of SRV susceptibility and resistance in certain inbred mice.